Abstract Number: Esoc2026a1195 Cortical Surface Area Partially Mediates the Effect of Genetically Predicted C-Reactive Protein Levels on Vascular Dementia

Abstract Background and aims Emerging evidence suggests inverse associations between circulating C-reactive protein (CRP) levels and dementia risk in certain contexts. Whether similar associations extend to vascular dementia (VaD) and the neural substrates remains unclear. Given that cortical morphometry is a key structural correlate of cognitive impairment, we investigated whether genetically predicted CRP levels causally influence cortical structure and mediate VaD risk. Methods Two-sample Mendelian randomization (MR) was performed using genome-wide association study summary statistics for CRP, global and regional brain imaging-derived phenotypes (IDPs), and VaD. Two-step MR mediation analysis quantified the indirect effects of CRP via cortical morphometry on VaD. Results Genetically predicted CRP levels were inversely associated with VaD risk (odds ratio OR=0.749, p=0.001) and its subcortical subtype (OR=0.711, p=0.010). Global cortical surface area was positively associated with the risk of VaD (OR=1.32, p=0.008) and subcortical VaD (OR=2.08, p=2.01×10-4), mainly driven by inferior parietal (OR=4.55, p=3.82×10-5) and posterior opercular regions (OR=2.92, p=1.18×10-5). Higher CRP levels were causally associated with reduced cortical surface area in these regions (FDR-corrected p0.05). Mediation analyses indicated that regional cortical surface area partially mediated the effects of CRP on VaD risk, accounting for 17.8–29.3% of the total effect (p0.05). Conclusions Genetically predicted CRP levels are associated with cortical surface area and lower VaD risk, with regional cortical structure partially mediating this association. These findings suggest that CRP-related biological processes may reflect context-dependent immune or systemic states relevant to vascular cognitive impairment, highlighting cortical surface area as a potential intermediate neuroanatomical biomarker. Conflict of interest Jie Zhang, Kaisi Ren, Haonan Xie, Mengsha Hu, and Shuchang Zhong: nothing to disclose.